Abstract 369: Epigenetic Regulation of Cardiomyocyte Proliferation and Regeneration by Swi/snf Complex Subunit Arid1a

Abstract

Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost few days after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A ( Arid1a ), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation around birth ( Arid1a cKO ) in mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a cKO hearts displayed increased expression of key cell cycle genes, and HIPPO target genes, suggesting Arid1a is required for cell cycle withdrawal in neonatal cardiomyocytes. When Arid1a was inducibly removed from adult cardiomyocytes ( Arid1a icKO ), hearts had normal gross morphology without visible signs of cardiac pathology. Next, we performed IR injury on Arid1a icKO mice and observed increased cell cycle activity in mutant border zone cardiomyocytes. To further explore the mechanisms by which Arid1a functions in cardiomyocytes, we are currently performing ChIP-Seq and protein interaction studies. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Suppression of Arid1a after ischemic injury may prove to be a novel target for therapeutics to enhance cardiac regeneration.